My medical career has been strongly focused towards neuro-oncology. Through clinical research during medical school and residency, then moving on to basic science research during my fellowship, I have been driven by the need to cure children with brain tumors. Having recently completed my fellowship in Pediatric Hematology/Oncology, I am now seeking to continue my line of investigation through a Mentored Clinician Scientist Award. I feel that the University of California, San Francisco provides an excellent environment in which to do so. My mentor, William Weiss MD,PhD, has a nurturing lab that will allow me to reach my goals. [My co-mentor Kevin Shannon has expertise in mouse models of cancer and has mentored several pediatric physician scientists with K08 awards.] In addition, through productive collaborations with Kevan Shokat (an expert in tyrosine kinases) and C. David James (an expert in brain tumor models), I believe I am uniquely situated to achieve my goals. My research focus is on malignant gliomas. Current therapies are inadequate, with most patients succumbing to their disease and survivors having significant long-term deficits. The Epidermal Growth Factor Receptor (EGFR) features prominently in this disease, through over-expression, amplification and mutation. EGFR-targeted therapy using small molecule inhibitors or monoclonal antibodies have shown only brief responses in a small fraction of patients. We believe that current targeted approaches fail because current inhibitors result in inadequate blockade of EGFR and recovery of downstream signaling pathways. Our preliminary data argues that irreversible EGFR inhibitors and combination therapy approaches can significantly improve therapeutic efficacy. In our proposed studies, we seek to further study these mechanisms and to investigate these approaches in a highly relevant in vivo model. PUBLIC HEALTH RELEVANCE: Malignant gliomas are an aggressive and common cancer in both children and adults. This research aims to improve therapy for these patients by understanding why current therapies fail and proposing novel strategies.